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1. The stereoselective S-oxidation and reduction pathways of flosequinan [(+/-)-7- fluoro-1-methyl-3-methylsulphinyl-4-quinolone] in rat were investigated in vitro. 2. Cytosol from both the liver and kidney catalysed the reduction of R(+)-flosequinan (R-FSO) and S(-)-flosequinan (S-FSO) to flosequinan sulphide (FS, 7-fluoro-1-methyl3- methylthio-4-quinolone). Flosequinan sulphone (FSO2, 7-fluoro-1-methyl-3-methylsulphonyl-4-quinolone) was not reduced to R-FSO or S-FSO. 3. Liver microsomes catalysed four different S-oxidation pathways in the presence of NADPH, namely oxidation of FS to R-FSO and S-FSO and from R-FSO and S-FSO to FSO2. The formation of R-FSO and S-FSO from FS each exhibited a biphasic kinetic pattern, indicating that at least two distinct enzymes were involved. The pathway from FS to R-FSO appeared mainly catalysed by flavin-containing monooxygenases (FMO). 4. S-oxidation of FS to R-FSO was more rapid than that of FS to S-FSO. S-oxidation of FS to either R-FSO or S-FSO in liver microsomes was more rapid than that of either RFSO or S-FSO to FSO2. 5. Microsomes from both the kidney and lung catalysed the stereoselective S-oxidation of FS to R-FSO, and FMO was likely to have participated in these reactions. [ABSTRACT FROM AUTHOR]

1. The biotransformation of 1-(3,4-dichlorobenzyl)-5-octylbiguanide (OPB-2045), a new potent biguanide antiseptic, was investigated in male beagle dogs. Urinary and faecal excretion of unchanged compound and metabolites were studied following a single subcutaneous injection of C-labeled compound at a dose of 1 mg kg. 2. Four urinary metabolites were structually identified using synthetic standards and orspectraldataas3,4-dichlorobenzoicacid,6-\[5-(3,4-dichlorobenzyl)-1-biguanidino hexanoic acid (DM-210), 4-\[5-(3,4-dichlorobenzyl)-1-biguanidino] butanoic acid (DM212) and 5-\[5-(3,4-dichlorobenzyl)-1-biguanidino] pentanoic acid (DM-213). 3. The predominant radioactive substances in the excreta were DM-213 and DM-210 at 26 1% and 25 5%, respectively, of the dose. No unchanged compound was detected in the urine, and in the faeces it was only 2% of the dose. [ABSTRACT FROM AUTHOR]

1. The metabolism of carteolol, a beta-adrenoceptor blocking drug, was investigated in male Sprague- Dawley rat liver microsomes. 2. The formation of 8-hydroxycarteolo l was the principal metabolic pathway of carteolol in vitro and followed Michaelis-Mente n kinetics with a Km=11.0 +/- 5. 4 muM and a Vmax=1.58 +/- 0.64 nmol/min/nmol P450 respectively (mean+/- SD, n = 5). Eadie-Hofstee plot analysis of carteolol 8-hydroxylase activity confirmed single-enzyme MichaelisMenten kinetics. 3. The cytochrome P450 isoforms involved in 8-hydroxylation of carteolol were investigated using selective chemical inhibitors and polyclonal anti-P450 antibodies. Quinine ( Ki = 0.06 muM ) and quinidine ( Ki=2.0 muM), selective inhibitors of CYP2D1, competitively inhibited 8-hydroxycarteolo l formation. Furthermore, only anti-human CYP2D6 antibody inhibited this reaction. 4. These results suggest that carteolol is metabolized to 8-hydroxycarteolo l by CYP2D1.The Km of carteolol for CYP2D1 in male rat liver microsomes was much greater than those of propranolol or bunitrolol, indicating that carteolol has a lower affinity for CYP2D1 compared with these other beta-adrenoceptor blocking drugs. [ABSTRACT FROM AUTHOR]